Autoimmune disorders result from an overactive immune response of the body working against its own cells (1). Almost all autoimmune diseases are chronic and have no permanent cure. Over 300 million patients across the globe suffer from these disorders. Women constitute around 70%-75% of all autoimmune patients.
Eotaxin-2 is a chemokine that promotes cell trafficking and regulates inflammatory activities at the CCR3 gene complex site especially by inducing chemotaxis of eosinophils (2-4), basophils (4), and Th2-type lymphocytes (5).
So far, Eotaxin-2 was well known in the context of allergy. It was well documented that there is a significant increase in the levels of Eotaxin-2 during the allergic response (6-8). Recently, the inventors discovered that Eotaxin-2 is also involved in autoimmune and inflammatory diseases (WO 2010/086854) As described in Ablin et al. (9), inhibition of Eotaxin-2 demonsrated a protective effect in the Rat model of Rheumatod arthritis. In addition it was observed that Eotaxin-2 blockade attenuated experimental autoimmune encephalomyelitis as published by Mausner et al. (10).
Scleroderma, or systemic sclerosis (SSc), is a chronic, rare multisystem autoimmune disease characterized by immune system activation, endothelial dysfunction, and an active fibrotic process involving fibroblasts (11). The earliest stage in the development of the scleroderma lesions is endothelial cell activation and vascular damage. This is followed by the migration of inflammatory cells, primarily, monocytes and then lymphocytes. Eventually, a population of fibroblasts is activated. The activated fibroblasts continue to produce the extracellular matrix that underlies the ultimate fibrotic pathology of scleroderma (11). Studies revealed that human dermal fibroblasts express constitutively mRNA of the Eotaxin 1, 2 and 3 (13). In addition, elevated levels of Eotaxin were observed in lung fibrosis and in a bleomycine induced sclerosis mice model (14). Knockout mice to Eotaxin and CCR3 develop significantly reduced lung fibrosis (14, 15).
The proinflammatory CCR3 binding chemokines Eotaxin 1, Rantes and MCP-3 belong also to the CC chemokine family and serve as ligands to the CCR3 receptor. They are also involved in the migration of immune cells, a fact that explains their efficacy in inflammatory preclinical models (16, 17).
Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic disease limited to the lungs, occurring in older individuals, more frequently men, and characterized by a dismal prognosis, with a median survival of 3 to 5 years since diagnosis. The clinical features characterizing IPF include shortness of breath, radiographically evident diffuse pulmonary infiltrates, and varying degrees of inflammation, fibrosis, or both on biopsy. The cause of IPF remains unknown, however mechanisms underlying the recruitment and proliferation of fibroblasts and immune cells cells as well as their pathologic differentiation are thought to be a hallmark to disease progression. In addition, there appears to be a large number of mediators involved in IPF progress including cytokines, chemokines, fibrogenic factors, coagulant proteins, oxidants, and regulators of apoptosis (18, 19). It addition, the deposition of extracellular matrix components including collagen is integral to this fibrotic process (20).
Management of the disease generally includes some combination of supportive care, e.g, supplemental oxygen, pulmonary rehabilitation, consideration for lung transplant evaluation, and identification and treatment of possible comorbidities (21). Pirfenidone (Esbriet) and Nintedanib are the only FDA/EMA approved treatment currently available for individuals with IPF (22-24). Pirfenidone has antifibrotic and anti-inflammatory properties in various in vitro systems and animal models of fibrosis.